Fibromodulin reduces scar formation in adult cutaneous wounds by eliciting a fetal-like phenotype

Zhong Zheng, Aaron James, Chenshuang Li, Wenlu Jiang, Joyce Z. Wang, Grace X. Chang, Kevin S. Lee, Feng Chen, Emily A. Berthiaume, Yao Chen, Hsin Chuan Pan, Eric C. Chen, Weiming Li, Zhihe Zhao, Xinli Zhang, Kang Ting, Chia Soo

Research output: Contribution to journalArticle

Abstract

Blocking transforming growth factor (TGF)β1 signal transduction has been a central strategy for scar reduction; however, this approach appears to be minimally effective. Here, we show that fibromodulin (FMOD), a 59-kD small leucine-rich proteoglycan critical for normal collagen fibrillogenesis, significantly reduces scar formation while simultaneously increasing scar strength in both adult rodent models and porcine wounds, which simulate human cutaneous scar repair. Mechanistically, FMOD uncouples pro-migration/contraction cellular signals from pro-fibrotic signaling by selectively enhancing SMAD3-mediated signal transduction, while reducing AP-1-mediated TGFβ1 auto-induction and fibrotic extracellular matrix accumulation. Consequently, FMOD accelerates TGFβ1-responsive adult fibroblast migration, myofibroblast conversion, and function. Furthermore, our findings strongly indicate that, by delicately orchestrating TGFβ1 activities rather than indiscriminately blocking TGFβ1, FMOD elicits fetal-like cellular and molecular phenotypes in adult dermal fibroblasts in vitro and adult cutaneous wounds in vivo, which is a unique response of living system undescribed previously. Taken together, this study illuminates the signal modulating activities of FMOD beyond its structural support functions, and highlights the potential for FMOD-based therapies to be used in cutaneous wound repair.

Original languageEnglish (US)
Article numbere17050
JournalSignal Transduction and Targeted Therapy
Volume2
DOIs
Publication statusPublished - Jan 1 2017

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ASJC Scopus subject areas

  • Cancer Research
  • Genetics

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